Ho et al. found that the small molecule LB-100, an inhibitor of protein phosphatase-2A (PP2A), in combination with anti-PD-1, induced CD8+ T cell-dependent tumor regression in a majority (complete response in half) of mice with established CT26 colorectal tumors, and protected complete responders from rechallenge. Mechanistically, the combination increased tumor infiltration by CD8+ T cells with enhanced effector and cytolytic functions. LB-100 also activated the mTORC1 pathway, reducing CD4+ T cell differentiation into Tregs and promoting Th1 cytokine secretion. LB-100 and anti-PD-1 prophylactically controlled B16 melanoma.
Mounting evidence suggests that inhibition of protein phosphatase-2A (PP2A), a serine/threonine phosphatase, could enhance anticancer immunity. However, drugs targeting PP2A are not currently available. Here, we report that a PP2A inhibitor, LB-100, when combined with anti-PD-1 (aPD-1) blockade can synergistically elicit a durable immune-mediated antitumor response in a murine CT26 colon cancer model. This effect is T-cell dependent, leading to regression of a significant proportion of tumors. Analysis of tumor lymphocytes demonstrates enhanced effector T-cell and reduced suppressive regulatory T-cell infiltration. Clearance of tumor establishes antigen-specific secondary protective immunity. A synergistic effect of LB-100 and aPD-1 blockade is also observed in B16 melanoma model. In addition, LB-100 activates the mTORC1 signaling pathway resulting in decreased differentiation of naive CD4 cells into regulatory T cells. There is also increased expression of Th1 and decreased expression of Th2 cytokines. These data highlight the translational potential of PP2A inhibition in combination with checkpoint inhibition.